Document 0343
 DOCN  M9590343
 TI    In vitro generation and characterisation of foscarnet-resistant HIV-1.
 DT    9509
 AU    Tachedjian G; Gurusinghe A; Hooker D; Deacon N; Mills J; Birch C;
       Macfarlane Burnet Centre for Medical Research, Fairfield,; Victoria.
 SO    Annu Conf Australas Soc HIV Med. 1994 Nov 3-6;6:154 (unnumbered
       abstract). Unique Identifier : AIDSLINE ASHM6/95291756
 AB    Foscarnet is a pyrophosphate analogue used in the treatment of CMV
       retinitis and acyclovir-resistant herpes simplex infections in AIDS
       patients. It is also an inhibitor of HIV-1 reverse transcriptase (RT),
       and therefore long-term administration in patients may result in the
       emergence of foscarnet-resistant (FosR) virus. To investigate the
       potential for FosR HIV to emerge in vivo we generated resistant strains
       by in vitro selection in MT-2 cells, starting from a clinical isolate
       (#237288) and a molecular clone of HXB-2. Strains were biologically
       cloned in the presence of different concentrations of foscarnet and
       compared to the original sensitive isolate with respect to
       susceptibility to a series of HIV inhibitors. The nucleotide sequence of
       the entire pol gene was also determined. Following 6 and 16 passages of
       #237288 and HXB-2 respectively in increasing concentrations of
       foscarnet, resistant strains able to replicate at 200 micrograms/ml of
       drug emerged. Nucleotide sequence analysis of four biological clones
       derived from resistant #237288 revealed single amino-acid substitutions
       Glu89-Lys or Leu92-Ile while resistant clones of HXB-2 had one
       significant change in the RT domain (Ser156-Ala). The positions of these
       changes in context of the three dimensional structure of the HIV RT will
       be presented. Compared to foscarnet-sensitive HIV-1, strains with the 89
       or 92 change showed hypersensitivity to azido-nucleoside analogues and
       non-nucleoside RT inhibitors, while no change in ddC and ddI
       susceptibility was observed. These results provide information on the
       mechanism of foscarnet resistance and have important implications for
       therapy with foscarnet.
 DE    Amino Acid Sequence/DRUG EFFECTS/GENETICS  Base Sequence/DRUG
       EFFECTS/GENETICS  Cloning, Molecular  Drug Resistance/GENETICS
       Foscarnet/*PHARMACOLOGY  Genes, pol/DRUG EFFECTS/GENETICS  Human
       HIV-1/*DRUG EFFECTS/GENETICS  Reverse Transcriptase/*ANTAGONISTS &
       INHIB/GENETICS  Virus Replication/DRUG EFFECTS/GENETICS  MEETING
       ABSTRACT

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).